The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4

Abstract

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking.

Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries].

Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families.

Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families.

Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.

Figure 1.. Box plot of melanoma thickness for pre-study versus prospective familial melanoma cases by CDKN2A/CDK4 mutation status.

The above figure shows the interquartile range and median thickness for pre-study (129 CDKN2A/CDK4 mutation carriers; 99 individuals with no mutation identified by whole exome sequencing) versus prospective (31 CDKN2A/CDK4 mutation carriers; 15 individuals with no mutation identified by whole exome sequencing) familial melanoma cases by mutation status. P-values were calculated from generalized linear models that account for relatedness of family members.

Figure 2.. Trends in tumor thickness for United States familial melanoma cases and general population.

The above figure shows changes in melanoma thickness over time for familial cases (National Cancer Institute [NCI] pre-study melanomas, NCI prospective melanomas) and the general population. Smoothed curves were produced for each group using the “lpoly” code in STATA 15 (College Station, Texas), which performs unadjusted kernel-weighted local polynomial regression. General population data was obtained from the Surveillance, Epidemiology, and End Results (SEER) 9 cancer registries. The per year fold change in tumor thickness is reported for each group using multivariable models adjusted for gender and age category (0–29, 30–49, 50–64, ≥65) (all cases in each group were from White patients).